title: The discovery and optimization of novel dual inhibitors of topoisomerase II and histone deacetylase.
abstract: A novel class of podophyllotoxin derivatives have been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities towards histone deacetylases and Topo II and their cytotoxicities in cancer cell lines were evaluated. The aromatic capping group connection, linker length and zinc-binding group were systematically varied and preliminary conclusions regarding structure-activity relationships are discussed. Among all of the synthesized hybrid compounds, compound 24 d showed the most potent HDAC inhibitory activity at a low nanomolar level and exhibited powerful antiproliferative activity towards HCT116 colon carcinoma cells at a low micromolar level. Further exploration of this series led to the discovery of potent dual inhibitor 32, which exhibited the strongest in vitro cytotoxic activity.
authors.affiliation: Institute of Drug Discovery and Development, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Bao
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Yu
authors.forename: Linjiang
authors.initials: L
authors.lastname: Tong
authors.forename: Yu
authors.initials: Y
authors.lastname: Luo
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Huang
authors.forename: Mingbo
authors.initials: M
authors.lastname: Su
authors.forename: Li
authors.initials: L
authors.lastname: Sheng
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
mesh_terms: D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000633:toxicity; D010655:Phenylenediamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010655:Phenylenediamines; D011994:Recombinant Proteins; D059005:Topoisomerase II Inhibitors; D000077337:Vorinostat; D006655:Histone Deacetylases; D004250:DNA Topoisomerases, Type II; D011034:Podophyllotoxin
keywords: Cancer; HDAC; Hybrid; Podophyllotoxin; Synergistic effect; Topoisomerase II